Cholesterol ester transfer protein CETP

Under the same conditions, tricyclo[5.3.1.0]undecanes are accessible from 5-sub-stituted 2-cyclohexen-l-one as 2-370 with a shorter tether by one CH2-group. Recently, another Michael/Michael/aldol transformation was employed by Paulsen and coworkers to obtain access to the central aromatic core of compounds as 2-376 (Scheme 2.89) [206]. It is of value that such products are thought to act as cholesterol ester transfer protein (CETP) inhibitors, and the application of these drugs should prevent reduction of the HDL-cholesterol level and therefore reduce the risk of coronary heart diseases [207]. 

In 1998 the REGRESS group published data, which showed that the TaqlB polymorphism in intron 1 of the cholesterol-ester transfer protein (CETP) gene predicts whether men with coronary artery disease would benefit from treatment with pravastatin or not [60]. Pravastatin therapy slowed the progression of coronary athero-... 

Cholesterol ester transfer protein (CETP) exchanges cholesterol ester (from HDL) with triglyceride (to HDL) and both lipoproteins may be cleared by the liver. 

Choiesteryi Ester Transfer Protein inhibitors Cholesterol ester transfer protein (CETP) is a glycoprotein that transfers choiesteryi ester from HDL (high density lipoprotein) to proatherogenic apolipoproteins (LDL—(low density lipoprotein). Its inhibition has beneficial effects at the level of HDL cholesterol. SC-71952 and torcetrapib are highly fluorinated CETP inhibitors. SC-71952 is a disymmetrical sulfide with 10 fluorine atoms. Torcetrapib contains three CF3 groups (Figure 8.61). ... 

The nascent HDL particles change shape and composition as they acquire additional free cholesterol by passive cellular diffusion of free cholesterol from cell membranes or from other plasma lipoproteins. HDL surface-localized LCAT progressively converts the free cholesterol on the surface of the particles to cholesterol ester, which occupies the core of the lipoprotein particle. This process converts the shape of the HDL particles from discoidal to spherical. The lipid unloading of HDL in the liver follows at least two pathways. In the first route, the cholesterol ester transfer protein (CETP) mediates cholesterol ester transfer from HDL to VLDL and LDL in exchange for triglyceride LDL in turn are taken up by the liver via the LDL receptor. In the second route, HDL binds to the scavenger receptor Bl, and cholesterol esters are selectively taken into the liver cells without internalization of HDL proteins (Fig. 15-2). 

The cholesterol esters of HDLs can also be transferred to VLDLs and LDLs through the action of the HDL-associated enzyme, cholesterol ester transfer protein (CETP). This has the added effect of allowing the excess cellular cholesterol to be returned to the liver through the LDL-receptor pathway as well as the HDL-receptor pathway. 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Kelkar, M.A., Pednekar, D.V., Pimple, S.R. and Akamanchi, K.G. (2004) 3D QSAR studies of inhibitors of cholesterol ester transfer protein (CETP) by CoMFA. CoMSlA and GFA methodologies. Med. Chem. Res., 13, 590-604. 

Other lipoproteins and from cell membranes and converts it to cholesterol esters by the lecithin.-cholesterol acyltransferase (LCAT) reaction. Then HDL either directly transports cholesterol and cholesterol esters to the liver or transfers cholesterol esters to other lipoproteins via the cholesterol ester transfer protein (CETP) Ultimately, lipoprotein particles carry the cholesterol and cholesterol esters to the liver, where endocytosis and lysosomal digestion occur. Thus, reverse cholesterol transport (i.e., the return of cholesterol to the liver) is a major function of HDL. 

Fig. 34.16. Functions and fate of FiDL. Nascent FiDL is synthesized in liver and intestinal cells. It exchanges proteins with chylomicrons and VLDL. HDL picks up cholesterol (C) from cell membranes. This cholesterol is converted to cholesterol ester (CE) by the LCAT reaction. HDL transfers CE to VLDL in exchange for triacylglycerol (TG). The cholesterol ester transfer protein (CETP) mediates this exchange. PL = phospholipids.

Fig. 34.17. Function of cholesterol ester transfer protein (CETP). CETP transfers cholesterol esters (CE) from HDL to VLDL in exchange for triacylglycerol (TG).

Mice and other animal models of disease are often poor mimics of the human condition. However, the expression of human genes in these animals can initiate development of the disease. In mice, the distribution of cholesterol between low-density lipoproteins (LDL) and high-density lipoproteins (HDL) is quite distinct from that in humans. However, if the human enzyme, cholesterol ester transfer protein (CETP) is expressed in mice, the ratio of LDL HDL becomes more human in profile. Inhibition of CETP is a target for antiatherosclerotic drags and there now exists an animal model in which to test them. 

Moreover several candidate genes and their variations such as cholesterol ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic triglyceride lipase (HL), LDL-receptor, ATP binding cassette transporter Al (ABCAl), and lecithin-cholesterol acyltransferase (LCAT) have been studied to demonstrate the individual s sensitivity toward developing CHD [102-108]. 

This experience is worth revisiting. Does it suggest that such large effects on HDL cholesterol cannot overcome the adverse effects of a modest increase in blood pressure Does that itself cast some doubt on the HDL hypothesis, or will other inhibitors of cholesterol ester transfer protein (CETP) reveal problems not associated with blood pressure Several major companies are advanced in their trials of CETP inhibitors. One, anacetrapib, has been found to be free of the mineralocorticoid-related blood pressure effects and is equi-potent with torcetrapib and another compound already in a large outcome trial. These inhibitors bind CETP to HDL and there are differences between the compounds to the extent of the reversibility of the binding [SEDA-32, 816]. 

Cholesterol ester transfer protein (CETP) A blood-borne protein that catalyzes the exchange of triglycerides in VLDL for cholesterol esters in HDL. 

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